The long term goal of this research project is to understand the molecular mechanisms mediating the anti-convulsant properties of cannabinoids and determine the role of endogenous cannabinoid receptors in modulating seizure termination and behavioral changes following chronic cannabinoid addiction and withdrawal. This research effort has discovered that the anti-convulsant properties of cannabinoids are mediated by CB1 receptor activation. Specific CB1 receptor antagonists, including SR141716A (SR1), can block the anti-convulsant effects of these compounds. These initial results suggest that the CB1 receptors mediating anti-convulsant activity have different properties in efficacy from CB1 receptors mediating behavioral effects. Our results also suggest an endogenous role for CB1 receptor activation in seizure termination. Chronic exposure to cannabinoids or acute withdrawal has also been shown to alter seizure susceptibility. By blocking endogenous CB1 receptor activation with antagonists and utilizing CB1 receptor activation during seizure discharge seizure may play an important role in preventing seizures from developing into continuous seizure activity, status epilepticus. The Central Hypothesis of this study is that the anti- convulsant effects of cannabinoids are mediated by CB1 receptor activation and that CB1 receptors play an important role in modulating seizure termination and hyperexcitability in cannabinoid addiction and withdrawal symptoms. This research project will combine a multi- disciplinary approach using interaction with other investigators in this research project to test the following Specific Aims: Aim 1: Determine if the anticonvulsant properties of cannabinoids are mediated by CB1 receptor activation; Aim 2: Determine if cannabinoid CB1 efficacies mediating anticonvulsant effects have different properties from CB1 receptor effects that mediate the behavioral effects of cannabinoids; Aim 3: Evaluate the effects of the anti-convulsant cannabinoids in CB1 knock out animals; Aim 4: Determine the role of endogenous CB1 receptor activation in the modulation of seizure termination and increased excitability in chronic cannabinoid use and withdrawal conditions; Aim 5: Determine the molecular mechanisms for CB1 receptor mediation of anticonvulsant effects ov cannabinoids and offer new treatment strategies and opportunities to potentially prevent clinical difficulties associated with marijuana addiction and acute withdrawal. Understanding the molecular mechanisms mediating CB1 receptor modulation of seizure termination and anticonvulsant action may provide an important insight into the endogenous function of CB1 receptors and provide an insight into the molecular mechanisms that may modulate some aspects of cannabinoid addiction and withdrawal phenomenon.